Revisiting the seed and soil in cancer metastasis

Abstract

Metastasis remains the overwhelming cause of death for cancer patients. During metastasis, cancer cells will leave the primary tumor, intravasate into the bloodstream, arrest at a distant organ, and eventually develop into gross lesions at the secondary sites. This intricate process is influenced by innumerable factors and complex cellular interactions described in 1889 by Stephen Paget as the seed and soil hypothesis. In this review, we revisit this seed and soil hypothesis with an emerging understanding of the cancer cell (i.e. seed) and its microenvironment (i.e. soil). We will provide background to suggest that a critical outcome of the seed-soil interaction is resistance of the stresses that would otherwise impede metastasis.

Fig. 1.

Tumor cells must resist stress in order to metastasize. Metastasis is thought to be a very inefficient process, in part, due to the number of stresses tumor cells must overcome in order to reach secondary sites and develop into gross metastatic lesions. Throughout each stage, tumor cells are confronted with various stresses, any of which may kill the cell. This results in a fragile balance between life and death for the cell. Only those tumor cells which can successfully manage the stress will survive. Depicted are examples of the various stresses tumor cells face during each stage of the metastatic process and some of the mechanisms the cell may use to deal with those stresses. Note that each stress and coping mechanism listed above are not exclusive to a particular stage of metastasis and likely apply to more than one of the stages. Cancer stem cells, those cells which are thought most able to resist the stresses of the metastatic cascade, are depicted in yellow. GF = growth factor; MMPs = matrix metalloproteinases; HSPs = heat shock proteins; CLICs = chloride intracellular ion channels.